Migration Inhibitory Factor
Macrophage migration inhibitor factor (MIF) was one of the first identified lymphokines [Bloom et al., Science 153: 80-82 (1966)] and is a pleiotropic cytokine released by macrophages, T-cells and the pituitary gland during inflammatory responses. It acts as a pro-inflammatory cytokine, playing a major role in endotoxin shock and counter-regulating the anti-inflammatory effects of dexamethasone [Bozza et al., J. Exp. Med. 189: 341-6 (1999)]. MIF promotes tumor necrosis factor alpha (TNF∀) synthesis, T-cell activation [Leech et al., Arthritis Rheum. 42: 1601-8 (1999)], enhances interleukin-1 (IL-1) and interferon gamma (IFN( ) production [Todo, Mol. Med. 4: 707-14 (1998)], impacts macrophage-macrophage adherence, up-regulates HLA-DR, increases nitric oxide synthase and nitric oxide concentrations, and inhibits Mycoplasma avium growth (U.S. Pat. No. 5,681,724). Certain of these features indicate that MIF also plays a role in the pathogenesis of rheumatoid arthritis (RA) (Id.). MIF is implicated in the activation of macrophages and counter-regulation of glucocorticoid activity [Chesney et al., Mol. Med. 5: 181-91 (1999)]. Recombinant forms of MIF and the DNAs encoding them have been previously described, see for example (WO 90/11301). MIF also has a reported role in the innate host response to staphylococcal and streptococcal exotoxins (Calandra et al., Proc. Natl. Acad. Sci. USA 95: 11383-8 (1998)).
MIF inhibition has been suggested for the treatment of acute lung injury to suppress the level of neutrophil attraction to the site of injury (Makita et al., Am J. Respir. Crit. Care Med. 158: 573-9 (1998)). MIF localizes to the cytoplasm of leukemic cells and has been linked to a role in leukemia associated inflammatory events (Nishihira et al., Biochem. Mol. Biol. Int. 40: 861-9 (1996)).
Several forms of MIF have been identified. The first characterized was that of Weiser et al., Proc. Natl. Acad. Sci. USA 86: 7522-6 (1989). This MIF (MIF-1) is 115 amino acids and 12.5 kDa (Id.). MIF-2 is a 45 kD protein identified in a human T-cell hybridoma clone (F5) (Hirose et al., Microbiol. Immunol. 35: 235-45 (1991)). The sequence of MIF-2 is very similar to MIF-1, but differs in that it is a more hydrophilic species than MIF-2 (Oki et al., Lymphokine Cytokine Res. 10: 273-80 (1991)).
MIF-3 is an 119 amino acid residue sequence (ATCC No. 75712; WO 95/31468). Antibodies and antagonists have been developed to MIF-3, which can be used to protect against lethal endotoxemia and septic shock or to treat ocular inflammations (WO 95/31468).
A related protein to MIF is the glycosylation-inhibiting factor (GIF), (Galat et al., Eur. J. Biochem. 224: 417-21 (1994)). The cDNA expressing the human form of GIF is described by Mikayama et al., Proc. Natl. Acad. Sci. U.S.A. 90: 10056-60 (1993). The amino acid sequences for MIF-1 and GIF are now recognized to be identical. The correct amino acid sequence is 114 amino acids and forms a 12,345 Da protein (Swiss-Protein accession number P14174).
Anti-MIF Antibodies
Polyclonal and monoclonal anti-human MIF antibodies have been developed against recombinant human MIF (Shimizu et al., FEBS Lett 381: 199-202 (1996); Japanese Patent No. 9077799A; German Democratic Republic Patent No. 230876A; European Patent No. 162812; and ATCC Accession Nos. 00201X0003, 1024674 and 1014477). One monoclonal antibody against human MIF (IC5/B) has been developed and utilized to study signals to mononuclear phagocytes in pseudolymphomas and sarcoidosis [Gomez et al., Arch. Dermatol. Res. (Germany) 282: 374-8 (1990); see also Weiser et al., Cell. Immunol. 90: 167-78 (1985)]. Additional human monoclonal anti-MIF antibodies were developed by Kawaguchi et al., J. Leukoc. Biol. 39: 223-232 (1986) and Weiser et al., Cell. Immunol. 90: 167-78 (1985). Anti-murine MIF monoclonal antibodies have also been prepared [See, e.g., Malomy et al., Clin. Exp. Immunol. 71: 164-70 (1988); and Liu et al., J. Immunol. 137: 448-55 (1986)].
Anti-MIF antibodies have been suggested for therapeutic use to inhibit TNF∀ release (Leech et al., 1999). As such, anti-MIF antibodies may have wide therapeutic applications for the treatment of inflammatory diseases. Related thereto, the administration of anti-MIF antibodies also reportedly inhibited adjuvant arthritis in rats (Leech et al., Arthritis Rheum. 41: 910-7 (1998)).
MIF has also been implicated in the pathogenesis of immunologically induced kidney disease. Lan et al., J. Exp. Med. 185: 1455-65 (1997) proposed the use of agents which block MIF activity to treat rapidly progressive glomerulonephritis in patients, and also suggested that MIF may be important in immune-mediated diseases generally.
Calandra et al., I. Inflamm. 47: 39-51 (1995) reportedly used anti-MIF antibodies to protect animals from experimentally induced gram-negative and gram-positive septic shock. Anti-MIF antibodies were suggested as a means of therapy to modulate cytokine production in septic shock and other inflammatory disease states (Id.).
Anti-MIF antibodies have been proposed for use to treat diseases where cellular/mucosal immunity should be stimulated or as a diagnostic or prognostic marker in pathological conditions involving the production of MIF (WO 96/09389).
MIF antagonists have been proposed to treat lymphomas and solid tumors which require neovascularization (WO 98/17314). WO 98/17314 by Bucala et al. reportedly describes inhibition of murine B cell lymphoma growth in vivo by a neutralizing monoclonal antibody against MIF administered at the time of tumor implantation (Chesney et al., 1999). Previous studies have shown that TH2 lymphocytes produce higher amounts of MIF upon stimulation than TH1 cells. (Bacher et al, 1996. PNAS 93:7849.) Since MIF is functionally involved in T-cell activation, neutralization of TH2 cell-derived may promote the ratio of TH1 to TH2 cells, thereby also prevent influencing host immunity against tumors (Chesney, 1999). Also, the use of anti-MIF antibodies for inhibiting proliferation of human endothelial cells has been reported [Chesney et al., Mol. Med. 5: 181-91 (1999); and Ogawa et al., Cytokine 12:309-314 (2000)]. Specifically, Ogawa et al. (2000) showed that certain anti-MIF antibodies directly block VEGF stimulated endothelial cell growth, presumably through neutralization of endogenously produced MIF.
Knock-out Animals for Use in Preparing Antibodies to Self-antigens
Transgenic animals have been prepared wherein foreign antigens are now expressed in the transgenic animal as a self-antigen. For example, a virus protein was expressed in a transgenic mouse model as a self-antigen in the pancreatic islets of Langerhans, as described by Oldstone et al., Cell 65: 319-31 (1991). Typically, however, it is difficult to produce antibodies against self-antigens or autoantigens such as MIF. Autoantigens are normal constituents of the body, which remain typically are not recognized by the immune system.
A knock-out (KO) mouse or animal is one in which the animal is homozygously deficient of a functional gene (Declerck et al., J. Biol. Chem. 270: 8397-8400 (1995)). In general, antibodies will not be raised against self-antigens nor against highly conserved domains of proteins that do not vary between species. However, certain KO mice have been produced in which monoclonal auto-antibodies against various autoantigens have been raised. Castrop et al., Immunobiol. 193: 281-7 (1995) reported preparation of the use of a KO mouse for the generation of monoclonal antibodies to T-cell factor-1 (TCF-1), which had been historically difficult to prepare antibodies to due to the extreme evolutionary conservation of TCF-1. Reportedly, because TCF-1 is highly expressed in thymus, intrathymic selection mechanisms will impose tolerance for TCF-1 in the immune system, likely through clonal deletion of TCF-1-reactive T-cells (Id.). The anti-TCF-1 antibodies were raised against a fusion protein comprising TCF-1 fused to maltose binding protein (MBP).
LaTemple et al., Xenotransplantation 5: 191-6 (1998) used a KO mouse to ∀1,3galactosyltransferase (∀1,3GT KO) to produce a natural, anti-Gal antibody. However, the antibody was only produced in low amounts.
Declerck et al. (1995) reported the preparation of anti-murine tissue-type plasminogen activator (t-PA) in a KO mouse, wherein the mouse lacked a functional t-PA gene. Declerck et al., also suggested that this approach could be applied to other classes of proteins allowing the generation of monoclonal antibodies against conserved epitopes, which could not be raised in wild-type animals because of their “self-antigen” nature. See also Declerck et al., Thromb. Haemost (Germany) 74: 1305-9 (1995).
To better study the biologic role of MIF, a mouse strain lacking MIF was generated by gene targeting in embryonic stem cells (Bozza et al., 1999). Using this mouse model, Bozza et al. determined that MIF is involved in a host response to gram negative bacteria induced sepsis.
Therefore, not withstanding what has been previously reported in the literature, there exists a need for preparing anti-MIF antibodies, especially monoclonal antibodies and fragments thereof with improved affinity and avidity for purposes of studying MIF function as well as regulating MIF activity. The methods of preparing the antibodies of this invention, as well as the antibodies themselves, can in turn be used to modulate MIF activity in diseases and conditions mediated by MIF, such as sepsis, rheumatoid arthritis, other autoimmune diseases, cancer, as well as injuries which induce MIF production.